In the United States, an estimated 2 million Americans both young and aged suffer equally from traumatic brain injury (TBI), which accounts for 30% of all injury-related deaths (Faul M, Xu L, Wanld M M, Coronado V G (2010) Traumatic brain injury in the United States: emergency department visits, hospitalizations, and deaths. Atlanta Ga.: Centers for Disease Control and Prevention, National Center for Injury Prevention and Control). However, aging is considered an independent risk factor for negative health outcomes after TBI. In fact, the incidence of TBI-related morbidities and mortally is higher in the aging population and exponentially increases with age (Hawkins B E, Cowart J C, Parsley M A, Capra B A, Eidson K A, Hellmich H L, Dewitt D S, Prough D S (2013) Effects of trauma, hemorrhage and resuscitation in aged rats. Brain Res 1496:28-35).
Recently, stem cell transplantation has been shown to be an effective regenerative therapy for functional and physiological improvement in animal models of brain disorders such as stroke, Parkinson's disease, Alzheimer's disease, and TBI (Lindvall O, Brundin P, Widner H, Rehncrona S, Gustavii B, Frackowiak R, Leenders K L, Sawle G, Rothwell J C, Marsden C D, Bjorkland A (1990) Grafts of fetal dopamine neurons survive and improve motor function in Parkinson's disease. Science 247:574-577; Clarkson E D (2001) Fetal tissue transplantation for patients with Parkinson's disease: a database of published clinical results. Drugs Aging 18:773-785; Isacson O, Costantini L, Schumacher J M, Cicchetti F, Chung S, Kim K (2001) Cell implantation therapies for Parkinson's disease using neural stem, transgenic or xenogeneic donor cells. Parkinsonism Relat Disord 7:205-212; Bjorklund L M, Sánchez-Pernaute R, Chung S, Andersson T, Chen I Y, Mc-Naught K S, Brownell A L, Jenkins B G, Wahlestedt C, Kim K S, Isacson O (2002) Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci USA 99:2344-2349; Mahmood A, Lu D, Lu M, Chopp M (2003) Treatment of traumatic brain injury in adult rats with intravenous administration of human bone marrow stromal cells. Neurosurgery 53:697-702; discussion 702-703; Yang M, Donaldson A E, Jiang Y, Iacovitti L (2003) Factors influencing the differentiation of dopaminergic traits in transplanted neural stem cells. Cell Mol Neurobiol 23:851-864; Yang M, Donaldson A E, Jiang Y, Iacovitti L (2003) Factors influencing the differentiation of dopaminergic traits in transplanted neural stem cells. Cell Mol Neurobiol 23:851-864; Bjugstad K B, Teng Y D, Redmond D E Jr, Elsworth J D, Roth R H, Cornelius S K, Snyder E Y, Sladek J R (2008) Human neural stem cells migrate along the nigrostriatal pathway in a primate model of Parkinson's disease. Exp Neurol 211:362-369; Muraoka K, Shingo T, Yasuhara T, Kameda M, Yuen W J, Uozumi T, Matsui T, Miyoshi Y, Date I (2008) Comparison of the therapeutic potential of adult and embryonic neural precursor cells in a rat model of Parkinson disease. J Neurosurg 108:149-159; Harting M T, Sloan L E, Jimenez F, Baumgartner J, Cox C S Jr (2009) Subacute neural stem cell therapy for traumatic brain injury. J Surg Res 153: 188-194; Liu Y P, Lang B T, Baskaya M K, Dempsey R J, Vemuganti R (2009) The potential of neural stem cells to repair stroke-induced brain damage. Acta Neuropathol 117:469-480).
An attractive cell therapy for regenerative medicine and wound healing is the use of mesenchymal stem cells (MSCs) derived from adipose tissue and their secretome. Human adipose derived stem cells (hADSCs) have the potential to proliferate, differentiate into different cell lineages, secrete an extensive secretome containing growth factors, cytokines, chemokines, microRNAs, and long noncoding RNA (lncRNA), and have therapeutic potential in TBI (Lendeckel S, Jödicke A, Christophis P, Heidinger K, Wolff J, Fraser J K, Hedrick M H, Berthold L, Howaldt H P (2004) Autologous stem cells (adipose) and fibrin glue used to treat widespread traumatic calvarial defects: case report. J Craniomaxillofac Surg 32:370-373; Xue S, Zhang H T, Zhang P, Luo J, Chen Z Z, Jang X D, Xu R X (2010) Functional endothelial progenitor cells derived from adipose tissue show beneficial effect on cell therapy of traumatic brain injury. Neurosci Lett 473: 186-191).
Of the many lncRNAs that are secreted, two are important for cellular differentiation, nuclear enriched abundant transcript 1 (NEAT1) and metastasis associated lung adenocarcinoma transcript 1 (MALAT1), because of their ability to assist in the alternative splicing of numerous pre-mRNA (Wapinski O, Chang H Y (2011) Long noncoding RNAs and human disease. Trends Cell Biol 21:354-361; Derrien T, Johnson R, Bussotti G, Tanzer A, Djebali S, Tilgner H, Guernec G, Martin D, Merkel A, Knowles D G, Lagarde J, Veeravalli L, Ruan X, Ruan Y, Lassmann T, Carninci P, Brown J B, Lipovich L, Gonzalez J M, Thomas M, Davis C A, Shiekhattar R, Gingeras T R, Hubbard T J, Notredame C, Harrow J, Guigó R (2012) The GENCODE v7 catalog of human long noncoding RNAs: analysis of their gene structure, evolution, and expression. Genome Res 22:1775-1789; Zhang B, Arun G, Mao Y S, Lazar Z, Hung G, Bhattacharjee G, Xiao X, Booth C J, Wu J, Zhang C, Spector D L (2012) The lncRNA Malatl is dispensable for mouse development but its transcription plays a cis-regulatory role in the adult. Cell Rep 2:111-123). Stem cells, which are in a proliferative, non-differentiating state, secrete numerous lncRNA, including NEAT1 and MALAT1. Stem cells, which are not differentiating, are apparently shedding the factors that would assist in differentiation until appropriate cues are in place.
However, the secretion of lncRNA does not exclude lncRNA uptake by adjacent cells, which could influence survival and regeneration of these cells by undisclosed modalities, including mRNA splicing, migration, and regulation of gene expression (Kim W S, Park B S, Sung J H, Yang J M, Park S B, Kwak S J, Park J S (2007) Wound healing effect of adipose-derived stem cells: a critical role of secretory factors on human dermal fibroblasts. J Dermatol Sci 48:15-24; Ikegame Y, Yamashita K, Hayashi S, Mizuno H, Tawada M, You F, Yamada K, Tanaka Y, Egashira Y, Nakashima S, Yoshimura S, Iwama T (2011) Comparison of mesenchymal stem cells from adipose tissue and bone marrow for ischemic stroke therapy. Cytotherapy 13:675-685; Sun J, Zhou H, Deng Y, Zhang Y, Gu P, Ge S, Fan X (2012) Conditioned medium from bone marrow mesenchymal stem cells transiently retards osteoblast differentiation by downregulating runx2. Cells Tissues Organs 196:510-522).
The majority of cell transplantation studies are performed in young animals. In fact, the inventors now understand that not only is endogenous neurogenesis affected in aging, a few reports suggest that the transplanted stem cells do not survive as well in the aged host (Conboy I M, Conboy M J, Wagers A J, Girma E R, Weissman I L, Rando T A (2005) Rejuvenation of aged progenitor cells by exposure to a young systemic environment. Nature 433:760-764; Carlson M E, Conboy I M (2007) Loss of stem cell regenerative capacity within aged niches. Aging Cell 6:371-382). However, less well studied is the mechanism of action of stem cells and if there may be alterations in migration of cells to various peripheral organs.